The proposed research will determine the electrophysiological effects of opiates and opioid peptides on hypothalamic neuroendocrine cells that secrete the peptide hormones, vasopressin and oxytocin. Endogenous opioid peptides regulate secretion of these hormones, and opiates have dramatic effects on this model neuroendocrine system. These hormones control several reproductive and homeostatic mechanisms (e.g., opiates depress lactation and parturition through actions in the hypothalamus). Parvocellular neurons and magnocellular neuropeptidergic cell. (MNCs) of the paraventricular and supraoptic nuclei (PVN and SON) will be studied with intracellular recording and staining; many of the recorded neurons will be immunocytochemically identified as oxytocinergic or vasopressinergic. The experimental system will be the in vitro hypothalamic slice preparation from adult rats and guinea pigs. Agonists and antagonists will be bath-perfused or microapplied with pressure through multibarrel micropipettes onto the slice, and effects on electrical properties will be determined. Based on previous studies, the main hypothesis to be tested is that opioid peptides and opiates act directly through a mu receptor to inhibit oxytocinergic neurons. This hypothetical mechanism of action is an increase in K+ conductance. One question to be examined is whether these agents have the same or different effect(s) on all PVN and SON neurons (i.e., neurons in different subnuclei and of different peptidergic content). We will determine whether opiates decrease the duration of action potentials, reduce responsiveness to other synaptic inputs, depress burst discharges and augment post-burst afterhyperpolarizations. The hypothesis that chronic morphine treatment leads to tolerance, dependence and withdrawal in the oxytocin system through direct alterations in membrane properties of oxytocinergic MNCs will also be tested. These electrophysiological hypotheses will be examined with intracellular recording (current-clamp and single-electrode voltage clamp). The proposed studies will provide fundamental information concerning opiate actions on the electrophysiology of identified cells in the magnocellular neuroendocrine system, a model regulatory site in the mammalian hypothalamus.